POTENTIAL ROLES OF COMPLEMENT IN ATHEROGENESIS

内皮损伤被认为是启动 动脉粥样硬化病变;随后，脂质积聚，巨噬细胞 募集、平滑肌细胞内膜增殖和纤维化 可能发生;最终血栓形成可能导致血管闭塞。 的 末端补体蛋白C5 b-9已在 人动脉粥样硬化斑块和损伤前内皮中的动脉粥样硬化斑块 在动脉粥样硬化的高胆固醇血症动物模型中的发展。 证据还表明，补体在加速免疫应答中起作用。 在人类心脏移植物中观察到的动脉粥样硬化。我们以前的工作 已经证明补体诱导促凝血反应， 内皮细胞，初步数据表明，沉积的内皮细胞， C5 b-9蛋白改变内皮-脂蛋白界面， 内皮细胞表面纤维蛋白溶解的调节。 本研究提案 探讨了补体激活可能 有助于动脉粥样硬化的进展。 具体目标是：（1） 确定补体是否影响内皮结合，或 LDL或乙酰化LDL的代谢，或改变内皮通透性 这些脂蛋白; 2）确定增加的机制 在对C5 b-9的反应中观察到HDL（及其载脂蛋白）的结合，以及 评价HDL/载脂蛋白结合改变对 内皮细胞胆固醇稳态; 3）确定是否 补体改变脂蛋白（a）的结合或代谢;和4） 表征补体诱导的纤溶酶原结合位点， 内皮细胞，并确定纤溶酶原激活是否是 促进或削弱这些细胞。 补体诱导的定义 内皮脂质代谢和纤维蛋白溶解的改变是 理解补体如何调节 动脉粥样硬化

Endothelial injury is believed to be a requirement for the initiation of atherosclerotic lesions; subsequently, lipid accumulation, macrophage recruitment, intimal proliferation of smooth muscle cells, and fibrosis may occur; ultimately thrombosis may result in vessel occlusion. The terminal complement proteins C5b-9 have been demonstrated in atherosclerotic plaques in man, and in endothelium prior to lesion development in a hypercholesterolemic animal model of atherosclerosis. Evidence also suggests that complement plays a role in the accelerated atherosclerosis observed in human cardiac allografts. our previous work has demonstrated that complement induces procoagulant responses from endothelial cells, and preliminary data suggests that deposition of the C5b-9 proteins alters both the endothelial-lipoprotein interface and endothelial surface regulation of fibrinolysis. This research proposal explores these two mechanisms by which complement activation may contribute to progression of atherosclerosis. Specific aims are: 1) to determine whether complement effects the endothelial binding or metabolism of LDL or acetylated LDL, or alters endothelial permeability to these lipoproteins; 2) to determine the mechanism of the increased binding of HDL (and its apoproteins) observed in response to C5b-9, and to evaluate functional effects of altered HDL/apoprotein binding on endothelial cell cholesterol homeostasis; 3) to determine whether complement alters binding or metabolism of lipoprotein(a) ; and 4) to characterize the complement-induced plasminogen binding sites on endothelial cells, and determine whether plasminogen activation is facilitated or impaired on these cells. Defining complement-induced alterations in endothelial lipid metabolism and fibrinolysis is fundamental to understanding how complement may modulate progression of atherosclerosis.